In school-age children previously diagnosed with depression as preschoolers, a key brain region involved in emotion is smaller than in their peers who were not depressed, scientists have shown in a new study published this week in the journal JAMA Psychiatry.

The research, led by a team at Washington University School of Medicine in St. Louis, also suggests that these brain changes may predict the risk of future bouts of depression, potentially giving researchers an anatomical marker to identify those at high risk for recurrence.

The brain region they focused on is known as the right anterior insula; each side of the brain has one insula, and they are thought to be involved in emotion, perception, self-awareness and cognitive function.

Past studies have shown that the insula is smaller in depressed adults compared with those of their peers who are not depressed. By using MRI scans and focusing on brain anatomy in children, the researchers hope to find clues to better diagnose and treat depression at its earliest stages and to identify individuals at higher risk for recurrent depressive episodes.

Answering the ‘million dollar question’

As part of the study, the investigators also found the same brain structure — the right anterior insula — is smaller in kids diagnosed with pathological guilt during their preschool years, providing evidence that excessive guilt is a symptom of depression related to the size of the insula.

“That’s not a complete surprise because for many years now, excessive guilt has consistently been a predictor of depression and a major outcome related to being depressed,” said first author Dr. Andrew C. Belden, PhD.

Pathological guilt can be a symptom of clinical depression, as well as other psychiatric disorders including anxiety, obsessive-compulsive disorder and bipolar disorder. Dr. Belden, an assistant professor of child psychiatry, said it’s relatively easy to spot the problem in children because they excessively blame themselves for things they’ve done — and haven’t done.

“A child with pathological guilt can walk into a room and see a broken lamp, for example, and even if the child didn’t break it, he or she will start apologizing,” Dr. Belden explained. “Even after being told he or she is not at fault, the child will continue to apologize and feel bad.”

The “million-dollar question,” he said, is whether depressed children become more prone to guilt or guilt-prone children are more likely to become depressed. Either way, Dr. Belden said, the discovery that pathological guilt is related to changes in the brain that increase the risk for recurrent depression could be a major step in better understanding the trajectory of depression.

Small right insula, high levels of guilt in preschool predict later depression

To reach their conclusions, the researchers followed a group of children in the Preschool Depression Study. The children were assessed for depression and guilt each year from ages 3-6. All of the children also had MRI brain scans about every 18 months from ages 7-13.

Results showed that the anterior insula (red) on each side of the brain was smaller in preschool kids diagnosed with depression and those who experienced excessive guilt at early ages.

In total, 47 children were diagnosed with depression during their preschool schools, while 82 were confirmed to not have depression during that same time period. Of those with depression, more than half – 55 percent – showed signs of pathological guilt, while only 20 percent of the non-depressed children had “excessive guilt.”

The researchers found that children with a smaller insula in the right hemisphere of the brain — related either to depression or excessive guilt — were more likely to have recurrent episodes of clinical depression as they got older.

“Arguably, our findings would suggest that guilt early in life predicts insula shrinkage,” Dr. Belden said. “I think the story is beginning to emerge that depression may predict changes in the brain, and these brain changes predict risk for recurrence.”

The research suggests that excessive guilt and depression may put preschoolers on a developmental trajectory that contributes to problems with depression later in childhood and even throughout life. Some children experience depression, recover and never have another episode, but others experience a chronic and relapsing course. Dr. Belden said it is important to identify those who are at risk for chronic and relapsing depression, as intervention during early childhood — a period of high brain neuroplasticity — could prevent future episodes.

Need for early identification, treatment

A previous study from the same group found that children diagnosed with depression as preschoolers were 2.5 times more likely to be clinically depressed in elementary and middle school than kids who were not depressed in preschool.

The research team would like to continue the study for at least five more years to assess longer-term outcomes. During that time frame, study subjects will pass through the high-risk period of adolescence, when mental disorders are most likely to emerge.

“We’re hoping to follow these children for several more years, perhaps even into adulthood,” said Dr. Belden. “On the immediate horizon is a look at the effects of some things that become more common during adolescent years as kids hit a high-risk time for substance and alcohol abuse and other problems that often co-exist with clinical depression. We want to see how those sorts of issues affect these children we’ve been following since preschool.”

Studies indicate that depression affects approximately 2 percent of preschoolers in the United States today, though estimates vary widely and are thought to underestimate the number of children with clinically significant depressive symptoms.

Currently, there are no proven treatments for depression diagnosed in the preschool years. However, research strongly suggests that young children may benefit the most from mental health interventions, as the plasticity of their brain seems to make them more responsive to treatment effects.

Based on their findings, the team recommends adding depression screenings to regular medical checkups for preschoolers, but they acknowledged that such monitoring is unlikely to begin anytime soon.

“The reason it hasn’t yet become a huge call to action is because we don’t yet have any proven, effective treatments for depressed preschoolers,” explained Joan L. Luby, MD, director of Washington University School of Medicine’s Early Emotional Development Program and the study’s lead investigator. “Pediatricians don’t usually want to screen for a condition if they can’t then refer patients to someone who can help.”